Ultrasound in synthetic organic chemistry by n73md89

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									                                                                                                                            ession rare action compression




Ultrasound in synthetic organic chemistry
                                                                                                                        E
                                                                                                                                                5000 °C
                                                                                                                                                2000 atm


                                                                                                                                  REACHES      VIOLENT
                                                                                                                                UNSTABLE SIZE COLLAPSE




Timothy J. Mason
Sonochemistry Centre, School of Natural and Environmental Sciences, Coventry University, Coventry,
UK CV1 5FB


High-power ultrasound can generate cavitation within a                  by a European Society in 1990 and then other national groups
liquid and through cavitation provide a source of energy                has meant that the subject has expanded greatly over the last few
which can be used to enhance a wide range of chemical                   years.
processes. Such uses of ultrasound have been grouped under                 There are a range of applications for the uses of ultrasound in
the general name sonochemistry. This review will concen-                chemistry which include synthesis, environmental protection
trate on applications in organic synthesis where ultrasound             (the destruction of both biological and chemical contaminants)
seems to provide a distinct alternative to other, more                  and process engineering (improved extraction, crystallisation,
traditional, techniques of improving reaction rates and                 electroplating and new methods in polymer technology).
product yields. In some cases it has also provided new
synthetic pathways.                                                     2 Fundamental aspects
                                                                        Ultrasound is defined as sound of a frequency beyond that to
                                                                        which the human ear can respond. The normal range of hearing
1 Introduction
                                                                        is between 16 Hz and about 18 kHz and ultrasound is generally
The use of ultrasound in chemistry (sonochemistry) offers the           considered to lie between 20 kHz to beyond 100 MHz.
synthetic chemist a method of chemical activation which has             Sonochemistry generally uses frequencies between 20 and 40
broad applications and uses equipment which is relatively               kHz because this is the range employed in common laboratory
inexpensive. The driving force for sonochemistry is cavitation          equipment. However since acoustic cavitation can be generated
and so a general requirement is that at least one of the phases of      well above these frequencies, recent researches into sonochem-
the reaction mixture should be a liquid. When laboratory                istry use a much broader range (Fig. 1). High frequency
research in sonochemistry began it seemed to be mainly a                ultrasound from around 5 MHz and above does not produce
method of initiating intransigent reactions especially those            cavitation and this is the frequency range used in medical
which depended upon the activation of metallic or solid                 imaging.
reagents. Its development in the past 15 years however has
revealed that it has far wider applicability than this and also that      0        10      102        103   104      105               106                 107
it presents a significant scientific challenge to understanding its
underlying physical phenomenon—acoustic cavitation. The
ever expanding number of applications of sonochemistry in
synthesis has made the subject attractive to many experimen-
talists and interest has spread beyond academic laboratories into
industry and chemical engineering.1–5                                         Human hearing                           16Hz-18kHz
   It was in 1986 that the first ever International Symposium on
Sonochemistry was held at Warwick University UK as part of                    Conventional power ultrasound           20kHz-40kHz
the Autumn Meeting of the Royal Society of Chemistry.6 This
meeting was significant in that it was the beginning of serious               Range for sonochemistry                 20kHz-2MHz
interest in the uses of ultrasound in chemistry as a study in itself.
                                                                              Diagnostic ultrasound                   5MHz-10MHz
Of course sonochemistry dates back much further than this. Its
origins can be traced to the early part of this century with the
                                                                                            Fig. 1 Sound frequency ranges
discoveries of echo sounding and the mechanical use of power
ultrasound for emulsification. The formation of the Royal
Society of Chemistry Sonochemistry Group in 1987 followed                 Like all sound energy, ultrasound is propagated via a series of
                                                                        compression and rarefaction waves induced in the molecules of
                                                                        the medium through which it passes. At sufficiently high power
                                                                        the rarefaction cycle may exceed the attractive forces of the
                                  Professor Mason obtained a            molecules of the liquid and cavitation bubbles will form. These
                                  BSc (1967) in chemistry and           bubbles will grow over a few cycles taking in some vapour or
                                  PhD (1970) in organic chem-           gas from the medium (rectified diffusion) to an equilibrium size
                                  istry from Southampton Uni-           which matches the frequency of bubble resonance to that of the
                                  versity. After periods at Am-         sound frequency applied. The acoustic field experienced by the
                                  herst College, USA, York Uni-         bubble is not stable because of the interference of other bubbles
                                  versity and Bradford University       forming and resonating around it. As a result some bubbles
                                  he joined Coventry Polytechnic        suffer sudden expansion to an unstable size and collapse
                                  (now University) in 1975. He is       violently. It is the fate of these cavities when they collapse
                                  currently chairman of the RSC         which generates the energy for chemical and mechanical effects
                                  Sonochemistry group and Pres-         (Fig. 2). There are several theories which have been advanced to
                                  ident of the European Society of      explain the energy release involved with cavitation of which the
                                  Sonochemistry      and      was       most understandable in a qualitative sense is the ‘hot spot’
                                  awarded a DSc in 1996.                approach. Each cavitation bubble acts as a localised micro-
                                                                        reactor which, in aqueous systems, generates temperatures of

                                                                                  Chemical Society Reviews, 1997, volume 26                                  443
                                                                              3.1 The ultrasonic cleaning bath
                                                                              The simple ultrasonic cleaning bath is by far the most widely
                                                                              available and cheapest source of ultrasonic irradiation for the
                      rarefaction compression rarefaction compression
                                                                              chemical laboratory. Although it is possible to use the bath itself
                                                                              as a reaction vessel this is seldom done because of problems
                                                                              associated with corrosion of the bath walls and containment of
                                                                              any evolved vapours and gases. The normal usage therefore
                                                                              involves the immersion of standard glass reaction vessels into
                                                                              the bath which provides a fairly even distribution of energy into
                        ONE CYCLE                                             the reaction medium (Fig. 4). The reaction vessel does not need
                                                           5000 °C            any special adaptation, it can be placed into the bath, thus an
                                                           2000 atm           inert atmosphere or pressure can be readily maintained
                                                                              throughout a sonochemical reaction. The amount of energy
      BUBBLE      BUBBLE GROWS IN           REACHES      VIOLENT
      FORMS     SUCCESSIVE CYCLES         UNSTABLE SIZE COLLAPSE              which reaches the reaction through the vessel walls is low—
               BY RECTIFIED DIFFUSION                                         normally between 1 and 5 W cm22. Temperature control in
                                                                              commercial cleaning baths is generally poor and so the system
Fig. 2 Sound propagation in a liquid showing cavitation bubble formation      may require additional thermostatic control.
and collapse

several thousand degrees and pressures in excess of one
thousand atmospheres.                                                             reaction mixture
                                                                                                                       water + detergent
   In addition to the generation of extreme conditions within the
bubble there are also major mechanical effects produced as a
result of its rapid collapse. These are also of significance in
synthesis and include very rapid degassing of the cavitating                  stainless
liquid (in the rarefaction cycle the newly formed bubbles will                steel tank
fill with gas and be expelled from the liquid) and rapid                                                                                      optional
crystallisation (brought about through seed crystal generation                                                                                 heater
on implosion).

3 Laboratory equipment
The first requirement for sonochemistry is a source of                                                 transducers
ultrasound and whatever type of commercial instrument is used                                        bonded to base
the energy will be generated via an ultrasonic transducer—a                            Fig. 4 The ultrasonic cleaning bath in sonochemistry
device by which mechanical or electrical energy can be
converted to sound energy. There are three main types of
ultrasonic transducer used in sonochemistry: liquid-driven                    3.2 The ultrasonic probe
(effectively liquid whistles), magnetostrictive (based on the                 This apparatus allows acoustic energy to be introduced directly
reduction in size of certain metals, e.g. nickel, when placed in a            into the system rather than rely on its transfer through the water
magnetic field) and piezoelectric. Most of the current equip-                 of a tank and the reaction vessel walls (Fig. 5). The power of
ment used for sonochemistry utilises transducers constructed of               such systems is controllable and the maximum can be several
piezoelectric ceramics. These are brittle and so it is normal                 hundred W cm22. The probe system is more expensive than the
practise to clamp them between metal blocks for protection. The               bath and it is slightly less convenient in use because special
overall structure is known as a piezoelectric ‘sandwich’.                     seals will be needed if the horn is to be used in reactions which
Usually two ceramic elements are combined so that their overall               involve reflux, inert atmospheres or pressures above (or below)
mechanical motion is additive (Fig. 3). Piezoelectric trans-                  ambient.
ducers are very efficient and, depending on their dimensions,
can be made to operate over the whole ultrasonic range.
                                                                                           transducer
                                                                                             housing
                                                                                                                               generator
                                                  back mass                                 upper (fixed)
   securing bolt                                   of metal                                    horn
                                                                                                                          screw fitting
    piezo elements
                                                                                                                          at null point
                                                         electrical contact
electrical contact                                                                    detachable horn




                                                   front mass                          replacable
                                                     of metal                              tip

                                                                                       Fig. 5 The ultrasonic probe system in sonochemistry

        Fig. 3 Construction of a piezoelectric sandwich transducer
                                                                              4 An attempt to formulate some rules governing
   The two most common sources of ultrasound for laboratory
                                                                              sonochemical activity
sonochemistry are the ultrasonic cleaning bath and the ultra-
sonic horn or probe system.7 These generally operate at                       One of the earliest tenets of sonochemistry was that it is
frequencies of around 40 and 20 kHz, respectively.                            particularly good at assisting reactions involving solid reagents.

444       Chemical Society Reviews, 1997, volume 26
This is generally but not exclusively correct. A number of          enter the bubble and so should be volatile. The ‘concentration’
groups are attempting to gain an understanding of the               of cavitation bubbles produced by sonication using conven-
underlying principles of sonochemistry in order to be able to       tional laboratory equipment is very small and so overall yields
predict which type of reaction would be most susceptible to         in this type of reaction are low. Thus in the sonication of water
sonication. As a result of these efforts some guidelines have       small quantities of OH· and H· radicals are generated in the
been identified. An empirical classification of sonochemical        bubble and these undergo a range of subsequent reactions
reactions into three types was proposed by J.-L. Luche and was      including the generation of H2O2. The highly oxidising HO·
based upon the purely chemical effects induced by cavitation.8      species can react with other moieties in the bubble or migrate to
Other (mechanical) effects of cavitation bubble collapse (e.g.      the bulk solution where they have only transient existence. Such
emulsification) were considered to be physical rather than          radicals can have a significant effect on both biological and
chemical and judged to be ‘false’ sonochemistry. These so-          chemical species in aqueous solution and can be detected
called ‘false’ effects are often important and have been included   chemically.9 Organic solvents will also slowly decompose on
in the following interpretation of the three original types of      sonication but solvent decomposition is normally only a minor
reaction susceptible to sonochemical enhancement.                   contribution to any sonochemical reaction taking place in the
                                                                    medium.
Type 1 Homogeneous systems which proceed via radical or
                                                                       A synthetically useful reaction which takes place in the
       radical-ion intermediates. This implies that sonication
                                                                    collapsing bubble is the production of amorphous iron from the
       is able to effect reactions proceeding through radicals
                                                                    sonolysis of Fe(CO)5 (0.4 m) in decane under argon.10 Volatile
       and further that it is unlikely to effect ionic reactions.
                                                                    iron pentacarbonyl enters the bubble and is decomposed during
Type 2 Heterogeneous systems proceeding via ionic interme-
                                                                    collapse. The fact that an amorphous (rather than crystalline)
       diates. Here the reaction is influenced primarily
                                                                    material is produced confirms that very high temperatures are
       through the mechanical effects of cavitation such as
                                                                    generated in the bubble and that extreme cooling rates are
       surface cleaning, particle size reduction and improved
                                                                    involved. Conventional production of amorphous iron requires
       mass transfer. This is what has sometimes been
                                                                    rapid cooling from the vapour to solid state of the order of 106
       referred to as ‘false sonochemistry’.
                                                                    K s21. Sonolytic decomposition of iron pentacarbonyl in
Type 3 Heterogeneous reactions which include a radical
                                                                    pentane (a more volatile solvent) yields Fe3(CO)12 rather than
       pathway or a mixed mechanism i.e. radical and ionic.
                                                                    the metal indicating that the cavitation collapse is not so
       Radical reactions will be chemically enhanced by
                                                                    extreme in this solvent. Since this original report the study of
       sonication but the general mechanical effect referred to
                                                                    cavitation induced decomposition of iron and other metal
       above may well still apply. If the radical and ionic
                                                                    carbonyls has continued and expanded. In the case of molybde-
       mechanisms lead to different products ultrasound
                                                                    num hexacarbonyl the product is nanostructured molybdenum
       should favour the radical pathway and this could lead
                                                                    carbide which has proved to be an excellent dehydrogenation
       to a switch in the nature of the reaction products.
                                                                    catalyst.11
In this article the term sonochemistry will be used to encompass       Sucrose has a negligible vapour pressure and so cannot enter
any beneficial effect on synthesis induced by cavitation whether    the bubble during sonication. A study of the effect of sonication
it is chemical or physical.                                         on the rate of acid catalysed inversion of this material revealed
                                                                    no appreciable effect. It is tempting to conclude from this that
4.1 Reactions which exemplify the ‘rules’ of                        sonochemistry has no effect on involatile materials in solution.
sonochemistry                                                       This is not entirely correct because bubble collapse produces
4.1.1 Homogeneous liquid-phase reactions                            very large shear forces in the surrounding liquid capable of
Any system involving a homogeneous liquid in which bubbles          breaking the chemical bonding in polymeric materials dissolved
are produced is not strictly homogeneous, however, in sono-         in the fluid.1 Over the last few years, increasing interest has
chemistry it is normal to consider the state of the system to       been shown in this procedure since the net result of polymer-
which the ultrasound is applied. Sonochemical syntheses in          chain rupture is a pair of macroradicals, which may recombine
homogeneous conditions are not extensively reported which           randomly (resulting in a reduction in molar mass and possibly
suggests that cavitation is less effective in promoting reactions   leading to a monodispersed system) or act as a radical site on
under these conditions. The few studies which have appeared         which to polymerise another monomer added to the solution
indicate that sonochemical effects generally occur either inside    (resulting in block copolymerization).
the collapsing bubble where extreme conditions are produced,           Small accelerations, in the range 4–15%, have been found for
at the interface between the cavity and the bulk liquid where the   the rate of acid catalysed hydrolysis of a number of esters of
conditions are far less extreme or in the bulk liquid immediately   carboxylic acids.1 In the case of methyl ethanoate the effects (at
surrounding the bubble where the predominant effects will be        23 kHz) were attributed to the increased molecular motion
mechanical (Fig. 6).                                                induced by the pressure gradients associated with bubble
                              IN THE CAVITY                         collapse. Similarly, the hydrolysis of the 4-nitrophenyl esters of
                              extreme conditions                    a number of aliphatic carboxylic acids at 35 °C showed
                                                                    ultrasonically (20 kHz) induced rate enhancements which were
                                                                    all in the range of 14–15% (Scheme 1). The activation energy
                                                                    for the hydrolysis of each of the substrates varied considerably
                                                                    with the alkyl substituent (R = Me, Et, Pri, But) on the
                                                                    carboxylic acid and so the uniform increase in rate could not be
                                       AT THE INTERFACE             associated with any cavitational heating effect. Here again, the
                                       intermediate temperatures
                                                                    modest sonochemical effect was considered to be the result of
                                       and pressures
                                                                    mechanical effects.
                                                                             O
                                                                     R   C                      H2O           O
                                      IN THE BULK MEDIA                                                            + HO         NO2
                                                                             O            NO2         R   C
                                      intense shear forces
                                                                                                              OH
             Fig. 6 Cavitation in a homogeneous liquid                                            Scheme 1

  In order for a chemical to experience the extreme conditions        The effect of ultrasonic irradiation on the hydrolysis of
generated inside the cavitation bubble during collapse it must      2-chloro-2-methylpropane in mixed aqueous ethanolic solvents

                                                                                 Chemical Society Reviews, 1997, volume 26        445
of different compositions revealed more evidence for the              showed no sign of re-agglomeration even after being allowed to
influence of mechanical effects.1 The rate enhancement induced        stand for a period of 24 h.
by ultrasound (at 20 kHz) was found to increase with increase in
the alcohol content and to decrease as the reaction temperature           LARGE PARTICLES                         SMALL PARTICLES
was raised. A maximum rate increase of 20-fold was observed                     fragmentation
at 10 °C in 50% (m/m) solvent composition. This composition                                                                           surface
is closely coincident with the structural maximum for the binary                                                                      erosion
ethanol–water solvent system. It is logical to suppose that if the
sonochemical enhancement is associated with solvent disrup-
tion then the maximum effect would be observed at this
composition.

4.1.2 Heterogeneous systems
In any heterogeneous system cavitation which occurs in the
liquid phase will be subject to the same conditions as have been
described above for homogeneous reactions. There will be a              surface cavitation
                                                                         due to defects                                   violent collision
difference however when bubbles collapse at or near any
interface and this will depend upon the phases involved.                              Fig. 8 Cavitation in a particulate medium
   If cavitation bubbles are formed at or near to any large solid
surface the bubble collapse will no longer be symmetrical. The           The O-alkylation of 5-hydroxychromones is a difficult
large solid surface hinders liquid movement from that side and        process probably as a result of hindrance to ionisation caused by
so the major liquid flow into the collapsing bubble will be from      hydrogen bonding between the carbonyl and OH group coupled
the other side of the bubble. As a result of this a liquid jet will   with some dispersion of the resulting phenoxide O2 charge.
be formed which is targeted at the surface with speeds in excess      Thus, using 5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic
of 100 m s21 (Fig. 7). The mechanical effect of this is equivalent    acid ethyl ester as substrate in N-methylpyrrolidinone (NMP) a
to high pressure jetting and is the reason why ultrasound is so       low yield (28%) of the O-propyl product is obtained after 1.5 h
effective in cleaning. Depending upon the conditions used this        at 65 °C using 1-iodopropane and potassium carbonate as base
powerful jet can activate surface catalysis, force the impregna-      (Scheme 2).7 The yield was greatly increased under sonication
tion of catalytic material into porous supports and generally
increase mass and heat transfer to the surface by disruption of            OH     O                                    OR      O
interfacial boundary layers.                                                                      PrnI/K2 CO3

                                                                                                      NMP
                                      ASYMMETRIC COLLAPSE                         O     COOEt                                  O      COOEt

                                       improved mass transport                                       Scheme 2
                                           surface cleaning
                                                erosion               (probe 20 kHz) and the scope of the reaction was expanded by
                                                                      using a range of different haloalkanes (Table 1). Power
                                             Inrush of liquid         ultrasound would be expected to be effective in enhancing this
                                             from one side of         reaction via the reduction of the particle size of K2CO3 powder.
                                             collapsing bubble        This factor was investigated by first sonicating NMP containing
                                                                      K2CO3 at 65 °C. The appropriate proportions of 1-iodopropane
                                                                      and chromone were then added to the resulting very fine
                                                                      suspension and the reaction was run under conventional
                                                                      conditions. This resulted in around 90% product formation in 90
                                                                      min at 65 °C, a reactivity similar to that obtained under
      MICROJET FORMATION                                              continuous ultrasonic irradiation except that the reaction was
                                                                      approaching a definite limit at 90% yield. The fall-off suggests
               Fig. 7 Cavitation near to a solid surface              that the surface of the remaining K2CO3 had become deacti-
                                                                      vated, and this was confirmed when sonication of the residual
   For this reason the use of ultrasound in conjunction with          mixture rapidly completed the reaction.
almost any electrochemical process will be beneficial and has
been the subject of extensive study. The subject has become           Table 1 O-Alkylation of a hydroxychromone
known as sonoelectrochemistry.12 The particular advantages
which accrue include (a) degassing at the electrode surface, (b)        Alkyl group       Yield (stirred) (%)       Yield (sonicated) (%)
disruption of the diffusion layer which reduces depletion of
electroactive species, (c) improved mass transport of ions across       PrnI              28                        100
the double layer and (d) continuous cleaning and activation of          BunI              57                         97
the electrode surfaces. All of these effects combine to provide         BnBr              59                         97
enhanced yield and improved electrical efficiency.                    a GLC yields, 90 min in NMP at 65 °C, sonication with 20 kHz probe

   When the solid is particulate in nature, cavitation can produce    system.
a variety of effects depending on the size and type of the
material (Fig. 8). These include mechanical deaggregation and            A study of the Ullmann coupling reaction has provided
dispersion of loosely held clusters, the removal of surface           evidence that the mechanical effects of surface cleaning coupled
coatings by abrasion and improved mass transfer to the surface.       with an increase in surface area cannot fully explain the extent
Mechanical deagglomeration is a useful processing aid and is          of the sonochemically enhanced reactivity. The reaction of
illustrated in the effect of sonication (in a bath) of titanium       2-iodonitrobenzene to give a dinitrobiphenyl using conven-
dioxide pigment in water. A powder sample made up in water            tional methodology requires heating for 48 h and the use of a
consisting initially of agglomerates (volume mean diameter ca.        tenfold excess of copper powder (Scheme 3). The use of power
19 mm) was rapidly broken apart ( < 30 s) to provide a limiting       ultrasound affords a similar (80%) yield in a much shorter time
size of 1.6 mm particles. Furthermore, the sonicated sample           (1.5 h) using only a fourfold excess of copper.7 During these

446      Chemical Society Reviews, 1997, volume 26
               NO2                                NO2                    support, possibly by masking them through cavitationally
                                  Cu                                     induced cyanide absorption.
                     I
                             DMF/60 °C                                                                                 CH3

                                                   NO2

                                 Scheme 3                                                                                                         stir 24 h
                                                                                                                           CH2                        75%
studies it was observed that the average particle size of the
copper fell from 87 to 25 mm but this increase in surface area
was shown to be insufficient to explain the large (50-fold)                    CH2Br
enhancement in reactivity produced by ultrasonic irradiation.                               KCN/Al2O3
The studies suggested that sonication assisted in either the
breaking down of intermediates and/or the desorption of                                            CH3
products from the surface. An additional practical advantage                                                                   CH2CN
was that sonication prevented the adsorption of copper on the                                                                                  sonicate 24 h
walls of reaction vessels, a common problem when using                                                                                              77%
conventional methodology.
   The collapse of cavitation bubbles at or near the interface of
immiscible liquids will cause disruption and mixing, resulting                                               Scheme 5
in the formation of very fine emulsions (Fig. 9). This is
essentially a mechanical effect but it has been utilised in the             The same group have reported an example of sonochemical
hydrolysis of benzoate esters where the emulsion was produced            switching in a homogeneous reaction. The decomposition of
by a probe system.13 Using 10% NaOH the conventional                     lead tetraacetate in acetic acid the presence of styrene at 50 °C
hydrolysis (Scheme 4) under reflux, gave a very low yield after          generates a small quantity of diacetate via an ionic mechanism.
90 min; however sonication at room temperature afforded near             Under otherwise identical conditions sonication of the mixture
complete hydrolysis in 1 h.                                              gives 1-phenylpropyl acetate predominantly through an inter-
                                                                         mediate methyl radical which adds to the double bond (Scheme
                                                                         6).15 These results are in accord with the proposition that radical
                                                                         processes are favoured by sonication.
                                                                                                                               OAc                      OAc
                                                            powerful
                                                            disruption                                           OAc                   OAc        AcO
                                                            of phase
                                                            boundary                  Pb(OAc)4
                                                                                                                           +                 +


                                                                                                             radical            mixed                ionic
                                                                                                            pathway            pathway              pathway

                                                                                                             Scheme 6
           Fig. 9 Cavitation in a two phase liquid medium
                                                                            Another example of sonochemical switching and is found in
                                                                         the Kornblum–Russell reaction (Scheme 7). 4-Nitrobenzyl
                Me                                       Me              bromide reacts with 2-lithio-2-nitro-propane via a predomi-
                                  10% NaOH                               nantly polar mechanism to give, as a final product, 4-nitrobenz-
     Me                  COOMe               Me               COO–       aldehyde.16 An alternative SET pathway exists in this reaction
                                                                         leading to the formation of a dinitro compound. Sonication
                Me                                       Me              changes the normal course of the reaction and gives preferen-
                                 Scheme 4                                tially the latter compound, in amounts depending on the
                                                                         irradiation conditions and the acoustic intensity.
   Other applications of sonochemically induced emulsification
are in phase transfer catalysis, emulsion polymerisation and two              NO2                NO2                                                    NO2
phase enzymatic syntheses.                                                                                                       –
                                                                                     stir                                  O           sonicate
                                                                                                        +              N         Li+
4.1.3 Reactions ‘switched’ by ultrasound                                             S N2                                               SRN1
                                                                                                                           O
An extremely good way of demonstrating that sonochemistry is
different from other methods of enhancing chemical reactions is           H     O                  Br
to find specific reactions for which ultrasound has changed the                                                                                           NO2
product distribution. The first report of a reaction exhibiting
‘sonochemical switching’ came from Ando et al.14 The system                                                  Scheme 7
consisted of a suspension of benzyl bromide and alumina-
supported potassium cyanide in toluene as solvent (Scheme 5).               A sonochemical switch has also been observed in the
The aim was to produce benzyl cyanide by nucleophilic                    formation of the indanone nucleus from o-allyl benzamides
displacement of the bromine by supported cyanide. Under                  (Scheme 8).17 The ketyl radical anion cyclizes to 2-methylin-
stirring alone the reaction provided diphenylmethane products            danone and liberates an amide ion which deprotonates the allyl
via a Friedel–Crafts reaction between the bromo compound and             moiety. The resulting carbanion then undergoes cyclization to
the solvent, catalysed by Lewis acid sites on the surface of the         a-naphthol. Under sonication the first step of the process is
solid phase reagent. In contrast, sonication of the same                 accelerated and the ketyl is generated much more rapidly so that
constituents produced only the substitution product, benzyl              only the cyclization to 2-methylindanone occurs.
cyanide. The explanation for this was based upon cavitation                The Kolbe electrolysis of cyclohexanecarboxylate in aqueous
producing a structural change to the catalytic sites of the solid        methanol generates a mixture of products in which bicyclohexyl

                                                                                    Chemical Society Reviews, 1997, volume 26                                 447
                                                                     OH                             Br                                         MgBr
                                                                                                                   Mg turnings
                                                                                        CH3   CH2   CH    CH3                      CH3   CH2   CH     CH3
                                                                               90%                                      ether
        O
                                            stirred
                                                                                                                 Scheme 10
            NR2
                   + Li/THF                                                          ultrasonic irradiation is able to initiate Grignard formation in
                                                                       O
                                                                                     under 4 min compared with several hours using the traditional
                                           ultrasound                                method involving periodic crushing of the metal.
                                                                               90%
                                                                                        The formation of cyclopropanes through the Simmons–Smith
                                                                                     reaction involving zinc dust and CH2I2 and an alkene suffers
                                      Scheme 8                                       from several experimental drawbacks some of the major ones
                                                                                     being the sudden exotherm which occurs after an unpredictable
predominates (49%). In the presence of ultrasound (38 kHz)                           induction period, foaming and the difficulties in removing
however the product distribution was changed quite sig-                              finely divided metal from the reaction products. The conven-
nificantly reducing the yield of bicyclohexyl to only 7.7%                           tional method for enhancing this reaction relies upon activation
(Scheme 9).12 The major products were the result of two                              of the zinc metal by using it in the form of a zinc–silver or zinc–
electron processes through a cyclohexane carbocation which                           copper couple and/or using iodine or lithium in conjunction
gave cyclohexene (34%) by elimination and cyclohexyl methyl                          with the metal. The experimental difficulties have been
ether (32%) by solvent attack. A characteristic of many                              eliminated using a sonochemical procedure where no special
sonoelectrochemical processes is that the average cell potential                     activation of the zinc was required and good and reproducible
under sonication is less than that required conventionally. In this                  yields were obtained using zinc metal in the form of mossy rods
case a current density of 200 mA cm22 could be maintained at                         or foil (Scheme 11).19
a potential of 7.3 V with ultrasound compared with 8.3 V under
                                                                                                         CH3(CH2)7CH    CH(CH2)7COOCH3
silent conditions.
                                                                                                                        Zn/CH2I2
                      –e–
            COO–                                      COO•
                                                                                                         CH3(CH2)7CH     CH(CH2)7COOCH3

                                   –CO 2
                                                                                                                 Scheme 11

                           .                                                            The dehydrogenation of tetrahydronaphthalene to naph-
                                                                                     thalene using 3% Pd/C in digol under the influence of sonication
                                                 single-electron product
                                                                                     is accelerated by ultrasonic irradiation (Scheme 12).20 The
                                                                                     conventional thermal reaction in digol at 200 °C reached 55%
                     –e–                                                             conversion in 6 h (but thereafter reaction ceased) and only 17%
                                                                                     reaction was obtained in the same time at the lower temperature
                                                                                     of 180 °C. Under sonication at 180 °C the reaction reached
                                                                                     completion in 6 h. Pulsed ultrasound (at 50% cycle) was as
                               +                                OCH3       +
                                                                                     effective as continuous sonication and even a 10% cycle gave
                                                                                     over 80% yield. These results offer considerable energy
                                                             two-electron products   savings, particularly on processes carried out on a large scale.
                                      Scheme 9                                                                         Pd/C
                                                                                                                       digol

5 Some applications of ultrasound in synthesis
                                                                                                                 Scheme 12
5.1 The activation of metals
Ultrasound can be used to accelerate reactions involving metals                         Surface activation is of great use in catalysis where metal
through surface activation which can be achieved in three ways                       powders such as nickel, which are generally poor catalysts, can
(a) by sonication during the reaction, (b) as a pre-treatment                        be activated by sonication before use. Normally, simple nickel
before the metal is used in a conventional reaction or (c) to                        powder is a reluctant catalyst for the hydrogenation of alkenes
generate metals in a different and more reactive form.                               yet ultrasonic irradiation offered a reactivity comparable with
   A classic use of ultrasound is in the initiation and enhance-                     Raney nickel.21 In this case, ultrasound gave an unexpected
ment of synthetic reactions involving metals as a reagent or                         decrease in surface area due to aggregation of particles, with
catalyst. One such example is the preparation of a Grignard                          electron micrographs indicating a smoothing of the nickel
reagent. A long-standing problem associated with Grignard                            surface. Auger electron spectroscopy revealed an increase in the
reagent synthesis is that in order to facilitate reaction between                    nickel/oxygen ratio at the surface. The explanation suggested
the organic halide and the metal in an ether solvent all of the                      was that abrasion from interparticle collisions removes the
reagents must be dry and the surface of the magnesium must be                        oxide layer of the nickel giving the observed increased
clean and oxide free. Such conditions are difficult to achieve                       reactivity. A simple pre-sonication of 3 mm nickel in ethanol
and so many methods of initiating the reaction have been                             prior to use is quite capable of converting this powder from an
developed most of which rely on adding activating chemicals to                       extremely poor into an acceptable catalyst for the conventional
the reaction mixture. A very simple method of initiating the                         hydrogenation of oct-1-ene.
reaction is by sonication of the reaction mixture in an ultrasonic                      The reduction of metal salts to a finely divided very reactive
bath which avoids the need for the addition of chemical                              free metal generally involves refluxing the metal salt in THF
activators. The quantitative effects of ultrasound on the                            with a very active metal like potassium. The conditions for the
induction times for the formation of a Grignard reagent using                        production of these so-called Rieke powders can be ameliorated
magnesium turnings in various grades of ether have been                              using ultrasound such that equally reactive metal powders can
examined (Scheme 10).18 Using damp, technical grade ether                            be produced using lithium in THF at room temperature. An

448      Chemical Society Reviews, 1997, volume 26
example of the use of sonochemically generated Rieke powders                      system. Sonication provides such a method which has been used
is in the preparation of organosilicon compounds (Scheme                          in the synthesis of peptides (Scheme 16).25 The methodology is
13).22                                                                            effective using different solvent combinations (Table 3).
                           Cl3SiH                                 SiCl3                               BOC       Gly   +    Phe     N2H2Ph
                                                                          (94%)
                       'Rieke' Ni powder

                                                                                                                              Papain
                                                                                                                          Aqueous emulsion
                            Cl3SiH
                                                              CN
    CH2   CHCN                                  CH3      CH               (93%)
                       'Rieke' Ni powder
                                                              SiCl3                                       BOC    Gly Phe      N2H2Ph

                                     Scheme 13                                                                    Scheme 16

   A novel method of generated finely divided zinc metal is by                    Table 3 Dipeptide synthesis in an aqueous emulsiona
the use of pulsed sonoelectrochemistry using an ultrasonic horn
as the cathode.23 Normal electrolysis of ZnCl2 in aqueous                                         Organic phase            Stir      Sonicate
NH4Cl affords a zinc deposit on the cathode. When the
electrolysis is pulsed at 300 ms on/off and the cathode is pulsed                                 Diethyl ether            71        89
                                                                                                  Light petroleum          12        62
ultrasonically at a 100 : 200 ms on/off ratio the zinc is produced
as a fine powder. This powder is considerably more active than                    aWater (75%) with organic solvent (25%) at 37 °C 12 h, 38 kHz ultrasonic
commercial zinc powder, e.g. in the addition of allyl bromide to                  bath.
benzaldehyde (Scheme 14).
                                                                                     Another and probably the most spectacular example of the
           O                                                  H    OH             correct choice of optimized sonicating conditions has been
           C                                                                      reported for the microbial conversion of cholesterol to chol-
               H             Br
                   +                                                      (82%)   estenone (Scheme 17).26 Optimum conditions involved irradia-
                                  'Electrochemical'
                                      Zn powder                                   tion pulses of 2.8 W power applied for 5 s each 10 min and this
                                                                                  gave a 40% yield increase.
                                     Scheme 14


5.2 Enzymatic syntheses
An area of sonochemistry which is deserving of far greater
attention is the use of ultrasound to modify enzyme or whole                                              Microbial
cell reactivity. High power ultrasound will break biological cell                                          action
walls releasing the contents but it can also denature enzymes. It                 HO                                  O
is therefore very important that when ultrasound is used in
                                                                                                                  Scheme 17
conjunction with biological material the conditions of sonica-
tion must be carefully regulated.
   Controlled sonication has been used to ‘stimulate’ a suspen-                   5.3 Phase transfer and related reactions
sion of baker’s yeast to provide an inexpensive source of sterol                  The effect of cavitation on a suspended solid has been described
cyclase (Scheme 15, Table 2).24 This technique provides an                        above (section 4.1.2). Such effects become very important in the
                                                                                  case of reactions involving solid–liquid phase transfer catalysis.
                                                                                  The N-alkylation of indole with RBr [R = CH3(CH2)11] in
                                      R
                                                                                  toluene at 25 °C in the presence of solid KOH produces a 19%
                                                                              R   yield in 3 h using tert-butylammonium nitrate (Scheme 18).
                                                                                  This yield is substantially improved by sonication to around
                           Brewer's                                               90% after only 80 min.27
                             yeast
    O
                                                                                                                 RBr/KOH (solid)
                                      HO
                                                                                                      N                                         N
                                     Scheme 15                                                         H                                            R

                                                                                                                  Scheme 18
enantioselective enzymatic synthesis of a sterol in gram
quantities. Significantly, sonication has no effect on the activity
of the isolated cell-free cyclase system, a result which                             In some cases sonochemistry can completely remove the
demonstrates how cell membrane disruption can occur without                       need for PTC as is the case in the generation of dichlorocarbene
damage to the contents.                                                           by the direct reaction between powdered sodium hydroxide and
                                                                                  chloroform at 40 °C using an ultrasonic bath.28 Under these
Table 2 Conversion of squalene oxide to sterol with baker’s yeast                 conditions styrene can be cyclopropanated in 96% yield in 1 h
                                                                                  when a combination of both sonication and mechanical stirring
Enzyme source            Conversion (%)           Enantiomer conversion (%)       is used. Significantly the yield is much reduced to 38% in 20 h
                                                                                  with sonication alone because the power of the bath is not
Whole yeast               9.5                     19                              sufficient to disperse the solid reagent into the dense chloroform
Pre-treated yeast a      41.9                     83.9                            (Scheme 19).
a Presonication at 0 °C using a probe system (20 kHz) for 2 h. b Enzymatic           One route to amino acids is via the synthesis of aminonitriles.
reaction at 37 °C, 12 h.                                                          The direct reaction between an aldehyde, KCN and NH4Cl in
                                                                                  acetonitrile leads to a mixture of products but in the presence of
  When an enzyme is used in a two phase synthesis one of the                      alumina and sonication the reaction can be made more specific
important requirements is an efficient emulsification/mixing                      (Scheme 20).29 In the case of benzaldehyde the yield of the

                                                                                            Chemical Society Reviews, 1997, volume 26                   449
                               NaOH (solid)/CHCl3
                                                                                                                      PPh3+ Br–        O
                                                                                   Cl
                                Room Temp.                                                                                         +
                                                                                   Cl                                 PPh3+ Br–        O

                                            Scheme 19

                                                                                                                                                      LiOH
                                                                                                                                                    H2O/CH2Cl2
                                                        O
                                        CN                   C                     CN
    O       H
        C                          H C       OH         H    C OH              H   C NH2
                KCN/NH4Cl
                                                  +                   +
                    CH3CN


                                            Scheme 20

target aminonitrile is poor under normal stirred conditions with                                                               Scheme 22
benzoin and hydroxynitrile predominating (Table 4). The
presence of alumina suspended in acetonitrile increases the                                      Trialkylboranes are generally obtained through the stepwise
proportion of aminonitrile but the overall results make it clear                              reaction of borane with an alkene. With hindered alkenes
that the optimum reaction conditions require the presence of                                  however the reaction is very slow. Sonication promotes rapid
suspended alumina together with sonication and then the yield                                 reaction even with highly hindered substrates (Scheme 23).32
of target aminonitrile reaches 90%.                                                           Synthetic applications of this technique include the hydrobor-
                                                                                              ation/oxidation of vinyl groups.
Table 4 Strecker synthesis of an aminonitrilea

    Conditions                     Cyanohydrin          Benzoin           Aminonitrile
                                                                                                                                                                B
    Stir                           38                   21                 6                               +         BH
    Stir + Al2O3                   19                    9                64
    Sonicate                       45                   22                23
    Sonicate + Al2O3                3                    7                90                               Neat 99% yield 1 h ultrasonic bath (5 h normal)
a   25 °C, 38 kHz ultrasonic bath.


5.4 Miscellaneous syntheses                                                                          BnO                                            BnO
Synthetic applications of the sonolysis of iron carbonyl which                                                                          HO                O
lead to useful ferrilactones synthons have been described                                              O
                                                                                                               O                                                    O
(Scheme 21). These are prepared easily and in good yields from
vinyl epoxides and either iron pentacarbonyl or, for conven-
ience and safety, diiron nonacarbonyl. The use of ferrilactones                                        OTBDMS                                             OTBDMS
together with ultrasonically assisted reactions of samarium
diodide and sodium phenylcyanide in natural product syntheses                                                      (i) 9-BBN , THF , ultrasound               89 %
have been reviewed.30                                                                                              (ii) NaOH , H2O2

                O                                                                                                              Scheme 23
        R
                     +       Fe2(CO)9
                                                                                                 Sonochemistry has been used to improve a Friedel–Crafts
                                                                                              alkylation reaction used for the synthesis of the anti-inflamma-
                                                        O
                                                                                              tory agent ibuprofen (Scheme 24).33 When performed under
                                         (CO)3Fe                                              classical conditions (2 h at 25 °C) the reaction afforded only
                                                        R O                                   17% yield and for this reason the normal synthesis is via a less
                                                                 (i) R′NH2 /Lewis acid        direct route. Under the influence of ultrasound, using a cleaning
                                                                                              bath, but under otherwise identical conditions the yield was
                                     CeIV                        (ii) CeIV
                                                                                              improved to 50%.
                         R                                                                                                                                              COOH
                                                      CO              R

                                                                                        NR′          OSO2CH3                                      AlCl3
                               O                            O                O                 CH3   CH    COOH           +
                     O
                                                        O
                                             R

                                            Scheme 21
                                                                                                                               Scheme 24
   A rather difficult double Wittig reaction (Scheme 22) has
been effected with enhanced efficiency under sonication.31 The
                                                                                              6 Conclusions
process constitutes a novel type of annelation of an aromatic
ring when applied to o-quinones. It is possible to considerably                               Sonochemistry is an expanding field of study which continues
simplify experimental procedures with ultrasound which allows                                 to thrive on outstanding laboratory results.34 Applications can
the use of bases which are insensitive to moisture or air.                                    be found over a range of chemical systems, however it is in

450             Chemical Society Reviews, 1997, volume 26
heterogeneous reactions that sonochemical syntheses are most                 9 P. Riesz, Free radical generation by ultrasound in aqueous solutions of
widely developed. The potential improvements afforded by                       volatile and non-volatile solutes, Advances in Sonochemistry, ed. T.
sonication suggest that all chemical laboratories nowadays                     J. Mason, JAI Press, London, 1991, vol. 2, p. 23.
                                                                            10 K. S. Suslick, S.-B. Choe, A. A. Chichowlas and M. W. Grimstaff,
should be equipped with at least one small cleaning bath for
                                                                               Nature, 1991, 353, 414.
simple trials.                                                              11 T. H. Hyeon, M. M. Fang and K. S. Suslick, J. Am. Chem. Soc., 1996,
   While an empirical understanding of the subject has taken                   118, 5492.
sonochemists a long way towards predicting possible applica-                12 D. J. Walton and S. S. Phull, Sonoelectrochemistry, Advances in
tions considerable attention is currently being paid to gaining an             Sonochemistry, ed. T. J. Mason, JAI Press, London, 1996, vol. 4,
understanding of what actually goes on in the collapsing bubble                p. 205.
and in its immediate environment. In this area the chemists are             13 S. Moon, L. Duchin and J. V. Cooney, Tetrahedron Lett., 1979, 20,
finding very fruitful cooperation with engineers, physicists and               3917.
mathematicians making sonochemistry a truly interdisciplinary               14 T. Ando and T. Kimura, Ultrasonic organic synthesis involving non-
                                                                               metal solids, Advances in Sonochemistry, ed. T. J. Mason, JAI Press,
study.
                                                                               London, 1991, vol. 2, p. 211.
   Recent laboratory studies have revealed that for a few                   15 T. Ando, P. Bauchat, A. Foucaud, M. Fujita, T. Kimura and H. Sohmiya,
heterogeneous reactions high speed stirring has a similar effect               Tetrahedron Lett., 1991, 32, 6379.
to sonication.35 Thus in the cyclopropanation of styrene                    16 M. J. Dickens and J.-L. Luche, Tetrahedron Lett., 1991, 32, 4709.
(Scheme 19) the yield can be improved from 3% with magnetic                 17 J. Einhorn, C. Einhorn and J.-L. Luche, Tetrahedron Lett, 1988, 29,
stirring through 20% at 8000 rpm to 70% at 24 000 rpm. Such                    2183.
results are intriguing in that they confirm the importance of               18 J. D. Sprich and G. S. Lewandos, Inorg. Chim. Acta, 1982, 76, 1241.
mass transfer in sonochemistry and could suggest that high                  19 O. Repic and S. Vogt, Tetrahedron Lett., 1982, 23, 2729.
speed stirring involves hydrodynamic cavitation. Unlike sonica-             20 T. J. Mason, J. P. Lorimer, L. Paniwnyk, P. W. Wright and A. R. Harris,
                                                                               J. Catal., 1994, 147, 1.
tion however stirring at such very high speeds is unlikely to
                                                                            21 K. S. Suslick and D. J. Casadonte, J. Am. Chem. Soc., 1987, 109,
become a viable prospect in industry.                                          3459.
   Whatever the real laws of sonochemistry might be it is clear             22 W. L. Parker, P. Boudjouk and A. B. Rajkumar, J. Am. Chem. Soc.,
that sonochemistry has arrived, that sonochemistry is expanding                1991, 113, 2785.
and that chemists from all disciplines will find within the                 23 A. Durant, J. L. Delplancke, R. Winand and J. Reisse, Tetrahedron Lett.,
subject plenty that will be of interest to them.                               1995, 36, 4257.
                                                                            24 J. Bujons, R. Guajardo and K. S. Kyler, J. Am. Chem. Soc., 1988, 110,
7 References                                                                   604.
                                                                            25 K. Tadasa, Y. Yamamoto, I. Shimoda and H. Kayahara, J. Fac. Agric.
 1 T. J. Mason and J. P. Lorimer, Sonochemistry, Theory, Applications and      Shinshu Univ., 1990, 26, 21.
   Uses of Ultrasound in Chemistry, Ellis Horwood Publishers, Chichester,   26 R. Bar, Biotechnol. Bioeng., 1988, 332, 655.
   1988.                                                                    27 R. S. Davidson, Ultrasonics, 1987, 25, 35.
 2 Ultrasound, its physical, biological and chemical effects, ed. K. S.     28 S. L. Regen and A. Singh, J. Org. Chem., 1982, 47, 1587.
   Suslick, VCH, Mannheim, 1988.                                            29 T. Hanafusa, J. Ichihara and T. Ashida, Chem. Lett., 1987, 687.
 3 C. Einhorn, J. Einhorn and J.-L. Luche, Synthesis—Stuttgart, 1989,       30 C. M. R. Low, Ultrasonics Sonochemistry, 1995, 2, 153.
   787.                                                                     31 C. Yang, D. T. C. Yang and R. G. Harvey, Syn Lett., 1992, 799.
 4 Sonochemistry: The uses of ultrasound in chemistry, ed. T. J. Mason,     32 G. E. Keck, A. Palani and S. F. McHardy, J. Org. Chem., 1994, 59,
   Royal Society of Chemistry, Cambridge, 1990.                                3113.
 5 Current trends in sonochemistry, ed. G. J. Price, Royal Society of       33 C. Garot, T. Javed, T. J. Mason, J. L. Turner and J. W. Cooper, Bulletin
   Chemistry, Cambridge, 1993.                                                 des Societes Chimiques Belges, 1996, 105, 755.
 6 Special edition of the journal Ultrasonics covering the RSC Sonochem-    34 T. J. Mason and J.-L. Luche, Ultrasound as a new tool for synthetic
   istry Symposium, Warwick 1986, Ultrasonics, 1987, 25, January               chemists, Chemistry under Extreme or Non-classical Conditions, ed. R.
   issue.                                                                      van Eldick and C. D. Hubbard, John Wiley, New York, 1997, p. 317.
 7 T. J. Mason, Practical Sonochemistry, A users guide to applications in   35 J. Reisse, presented at NATO Advanced Study Institute on Sonochem-
   chemistry and chemical engineering, Ellis Horwood Publishers, Chich-        istry and Sonoluminescence, Leavenworth, Washington, USA, August
   ester, 1991.                                                                1997.
 8 J.-L. Luche, Sonochemistry, from experiment to theoretical con-
   siderations, Advances in Sonochemistry, ed. T. J. Mason, JAI Press,                                                  Received, 9th May 1997
   London, 1993, vol. 3, p. 85.                                                                                        Accepted, 30th June 1997




                                                                                      Chemical Society Reviews, 1997, volume 26                   451

								
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